Changes in Adaptive (Acquired) Immunity

Thymic involution: The thymus is the primary lymphoid organ in which bone marrow-derived T-lymphocyte precursors mature and differentiate into functional T lymphocytes. T lymphocytes that recognize antigens and have a moderate affinity for self-MHC molecules multiply in the thymus and enter the circulation. T lymphocytes that have excessive affinity for self-MHC molecules (> 95% of total T lymphocytes) are negatively selected and are eliminated in the thymus.

Contrary to the belief that thymic involution begins at puberty, the regression of the human thymus starts after birth and continues at a constant rate until middle age. Because the thymus appears to undergo premature aging, thymic involution has been deemed responsible for the age-related decrease in T-lymphocyte-mediated immune response. However, as the multiplication and release of mature lymphocytes become insufficient to compensate for the destruction of mature lymphocytes at the periphery, peripheral lymphoid organs take over the role of the thymus. Once the peripheral T-lymphocyte pool has been established early in life, the thymus may no longer be needed.

The effects of thymectomy in old age are inconsistent and usually mild. Moreover, in studies of aged animals, thymic transplantation or complete structural and functional thymic restoration by growth hormone does not significantly improve immune response.

The thymus produces several immunoregulatory hormones that affect the differentiation of T-lymphocyte precursors and possibly some of the activities of mature B and T lymphocytes. The concentration of thymic hormones decreases with age, and some of these hormones are no longer detected in the plasma of persons > 60. However, whether some aspects of immune senescence may be improved or prevented by supplementation with thymic hormones is unclear.

T-lymphocyte function: CD8⁺ T lymphocytes respond to class I MHC-antigen complexes and differentiate into cytotoxic effectors, whereas CD4⁺ T lymphocytes are restricted to class II MHC-antigen complexes and function as helper cells. T-helper lymphocytes promote intracellular killing by macrophages, antibody production by B lymphocytes, and clonal expansion of cytotoxic T lymphocytes.

Alterations of T-lymphocyte activities underlie much of the age-related decrease in protective immune response. Severe age-related defects in T-helper lymphocyte function, demonstrated by a weak allogeneic response, have been well documented. T-lymphocyte cytotoxicity and the proliferative response to mitogens and antigens also decrease significantly in elderly persons. This proliferative defect is attributed in part to the inability of T lymphocytes derived from aged organisms to secrete and respond to the growth factor interleukin-2. T lymphocytes from elderly persons are also hyporesponsive to stimulation mediated by certain co-receptors (eg, CD28 or CD2 surface molecules).

Alteration of T lymphocyte-mediated immunity in the elderly can be partly explained by an age-related decrease in the production of T-helper lymphocytes and cytotoxic precursors and by the different distribution of CD4⁺ and CD8⁺ T lymphocytes. Aging also leads to a dramatic increase in the proportion of antigen-experienced memory T lymphocytes with a concomitant decrease in naive T lymphocytes. Although the shift toward memory cells begins early in life, the progressive expansion of cells already committed to particular antigens and functionally different from naive T lymphocytes probably accounts for some aspects of immune senescence. Similar to B lymphocytes, T lymphocytes, especially CD8⁺ T lymphocytes, can become monoclonally or oligoclonally expanded in most healthy elderly persons. However, clonally expanded CD8⁺ T lymphocytes lack the CD28 surface molecule, a receptor essential for their optimal activation, which most likely contributes to immune senescence.

Novel or aberrant characteristics of T lymphocytes may appear with age. For example, T lymphocytes from elderly persons sometimes are activated by antigenic peptides that are not presented in association with self-MHC molecules. This finding in the elderly transgresses an essential law of immunology. Enhanced activity of particular T lymphocytes also occurs with age, as demonstrated by the high concentration of interleukin-6 (IL-6) and IL-10 in serum or in cultures of cells from elderly donors.

Understanding of the molecular mechanisms underlying the various defects in T-lymphocyte function is incomplete. Biochemical lesions accumulate along the pathways of signal transmission, activating genes implicated in T-lymphocyte activity. The pathogenesis of the multiplicity of age-related biochemical alterations in T lymphocytes is unexplained, but oxidative stress--a biologic phenomenon implicated in the process of senescence--can interrupt the signalization cascades at different sites and may be common to these various biochemical defects.

B-lymphocyte function: B lymphocytes produce antibodies and display them on the cell surface, where they serve as receptors for antigens. Specific recognition of foreign antigens by surface immunoglobulin receptors is the first step in the induction of humoral immunity. The bound antigen then undergoes endocytosis and is degraded into antigenic peptides and delivered to the plasma membrane in association with class II MHC proteins. T-helper lymphocytes recognize the MHC-antigen peptide complex and stimulate B-lymphocyte proliferation and differentiation into antibody-secreting cells.

With age, humoral immunity is generally impaired quantitatively and qualitatively. The amount of antibody produced in response to most foreign antigens decreases with age. Serum levels of IgM decrease with age, although the significance of this decrease is unknown. Serum levels of IgA and IgG increase, possibly reflecting increased production of antibodies in response to various intrinsic antigens (ie, autoantibodies) or to polyclonal B-lymphocyte activation by bacterial endotoxins.

With age, the number of circulating and antigen-responsive B lymphocytes decreases, but the amount of antibody produced on a per cell basis by responding B lymphocytes does not change. Thus, reduced specific antibody production appears to be due mainly to the presence of nonfunctional cells.

The quality of the humoral response may be more important than the quantity of antibodies produced. With age, B lymphocytes produce less protective antibodies (ie, antibodies that typically bind antigens less well). For example, the serum of elderly persons immunized with pneumococcal vaccine fails to opsonize with pneumococci, despite having a high content of specific antibodies.

Because most B-lymphocyte functions are regulated by T lymphocytes or their products, age-related decreases in humoral immunity due to intrinsic defects of B lymphocytes are difficult to differentiate from those due to T-lymphocyte defects.

Autoimmune reactivity: Although the immune response to exogenous antigens decreases with age, autoimmune reactivity increases. The percentage of autoreactive T and B lymphocytes and the frequency of autoantibodies directed against a wide variety of organ-specific and non--organ-specific antigens increase, indicating an age-related propensity to lose tolerance to self.

Normally, B lymphocytes expressing antibody receptors with high affinity to self are clonally deleted, rendered silent, or switched to a different specificity. With age, subsets of B lymphocytes may escape deletion or may be unable to revise their receptors and to delete their high affinity for self.

Autoimmune antibodies may also result from an immune response against self-molecules that have been altered by age-related processes (eg, oxidation, glycation) or released from anatomic sequestration. Polyclonal B- or T-lymphocyte activation by molecules of microbial origin may also be implicated in the aberrant self-recognition.